Antibody response to microbiota antigens is associated with alcohol-related liver disease severity and predicts mortality

Background and Aims: Alcohol-related liver disease (ALD) is associated with dysbiosis and translocation of gut microbial components, stimulating the innate immunity. The potential role of adaptive immune responses to gut microbiota has been less studied. We hypothesized that microbiota-specific antibody responses could be associated with ALD severity and outcomes. Approach and Results: Two hundred and seven patients with ALD were recruited at a single site and classified as steato-fibrosis, compensated cirrhosis Child–Pugh A, decompensated cirrhosis Child–Pugh B or C without (CP B/C) and with severe alcohol-related hepatitis (sAH). Biophysical and functional characteristics of antibodies specific for 11 classes of microbiota antigens were determined. High-dimensional analyses were used to compare levels and characteristics of antibodies between groups and explore their association with clinical outcomes. ALD severity was associated with increased levels of microbiota-specific antibodies and binding to Fc-gamma-receptors (FcgR), with the strongest relationships observed for levels of Staphylococcus aureus IgA and Candida albicans IgG and for binding of Escherichia coli IgG to FcgRIIb. Additional associations were observed between ALD severity and microbiota-specific antibody effector functions, suggesting regulation of their functional potential. Among patients with CP B/C and sAH, microbiota-specific antibody profiles predicted the occurrence of septic shock and mortality at 90 days, independently of the MELD score. Conclusions: The antibody response to microbiota is associated with ALD severity and predicts the risk of severe outcomes. These results suggest a role for immune complexes in ALD pathogenesis and that antibody profiling has potential as a biomarker for clinical management of ALD patients.